PROJECT SUMMARY Meningiomas are the most common primary intracranial tumor. Although many of these tumors are benign, presenting as WHO grade I lesions that can be cured with the standard therapeutic interventions of surgical resection and radiation therapy, recurrence is nevertheless relatively common. After failure of frontline treatment, there is unfortunately no effective therapy to offer patients who have progressive recurrent meningioma, and securing durable, long-term disease control in this setting has been challenging. New therapeutic approaches are needed for these cases. Modern genomic technologies have allowed for broad characterization of somatic gene mutations found in tumor cells in many different cancers. Recent work (by our team and others) in large cohorts consisting primarily of WHO grade I and untreated meningiomas has identified SMO, AKT1, KLF4, BAP1, TRAF7 and TERT promoter mutations in specific subsets of these tumors, in addition to the well-established NF2 inactivation that is characteristic of this neoplasm. To further characterize the clinical scenarios where we can derive maximal clinical benefit with therapeutic targeting of these alterations, we have assembled a large cohort of meningioma patients, which unlike prior discovery cohorts, are considerably enriched for specimens derived from recurrent, post-treatment and WHO grade-progressive tumors. Our proposed genomic analyses will therefore focus on understanding the molecular alterations across the clinical spectrum of this disease, and more importantly, have the potential to identify the genetic factors that drive meningiomas to relapse or undergo malignant transformation, targets which could be prioritized to maximize clinical impact. Thus, the successful execution of this work will provide important information to facilitate the design and interpretation of ongoing clinical trials for recurrent progressive meningioma.